Fluconazole

Fluconazole, which is absorbed from the stomach, has been shown to be effective in the treatment of the oral and esophageal forms of candidiasis in patients with acquired immunodeficiency syndrome. 

Fluconazole is used for superficial mucosal candidiasis and fungal skin infections. It should be used with caution in patients with renal and hepatic dysfunction. It is reported that teratogenicity is observed in animals hence it is not recommended for use in pregnant women.66 66g Adverse effects include abdominal pain and diarrhea. Alopecia has occasionally been reported in patients during prolonged use.67 

Class Synthetic, broad-spectrum bis-triazole antifungal agent with activity against Cryptococcus neoformans md Candida species  

Mechanism of Action Selectively inhibits fungal cytochrome P-450 sterol C-14 alpha-demethylation, leading to accumulation of 14 alpha-methyl sterols in fungi o u g 

Indications Treatment of oropharyngeal and esophageal candidiasis and may be effective for the treatment of serious systemic candidal infections Cryptococcal meningitis c  

Contraindications Hypersensitivity to fluconazole or to any of its excipients Caution should be used in patients with hypersensitivity to other azoles Should not be used with terfenadine orastemizole  

Warnings Anaphylaxis has been reported Patients who develop abnormal liver function tests should be monitored for development of more serious hepatic injury Immunocompromised patients who develop rashes should be monitored closely Cardiac events including torsade de pointes have been reported in patients on concomitant cisapride therapy  

Sample preparation 500 fji,L Plasma -I- 500 fj,L 10 p,g/mL IS in MeOH water 10 90-1- 250 p.L 1 M ammonium hydroxide, mix, add 5 mL ethyl acetate, mix, centrifuge. Remove the organic layer and add it to 1 mL 1 M HCl, mix, centrifuge. Remove the aqueous layer and add it to 1.5 mL 6 M ammonium hydroxide and 5 mL ethyl acetate, extract. Remove the organic layer and evaporate it to dryness under a stream of nitrogen at 40°, reconstitute the residue in mobile phase, inject eui ediquot. 

Schwartz, E.L. Hallam, S. Gallagher, R.E. Wiernik, P.H. Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia. Biochem.Pharmacol., 1995, 50, 923-928 

Sample preparation Condition a Bond-Elut CIS SPE cartridge with 2 column volumes MeOH and 2 column volumes 100 mM pH 6.0 sodium phosphate buffer. 1 mL Serum -l-100 p,L 100 p.g/mL IS in MeOH water 10 90 -I- 2 mL 100 mM pH 6.0 phosphate buffer, mix, add to the SPE cartridge, wash with 1 mL phosphate buffer, wash with 1 mL MeOH phosphate buffer 15 S5, dry under vacuum, elute with 500 (aL MeOH. Evaporate the eluate to dr3mess under a stream of nitrogen at 40°, reconstitute with 200 p,L mobile phase, filter, inject a 50 p,L aliquot of the filtrate. 

Mobile phase MeCN 25 mM pH 7.0 Tris-phosphate buffer 25 75 

Internal standard 2-(4-chlorophenyl)-l,3-bis(lH-l,2,4-triazol-l-yl)propan-2-ol (UK-48,134, Pfizer) (9.0) 

Molecular formula CiaHiaF NeO Molecular weight 306.3 CAS Reglatry No. 86386-73-4 

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Table 15 gives a sampling of other pharmaceuticals derived from hydraziae. Cefazolin, a thiadiazole tetrazole derivative, is one of the most widely used antibacterial dmgs in U.S. hospitals (see Antibiotics, P-LACTAMs). Procarbazine, an antineoplastic, is a monomethyUiydrazine derivative (220). Fluconazole has shown some promise in the treatment of AIDS-related fungal infections. Carbidopa is employed in the treatment of Parkinson s disease. FurazoHdone is a veterinarian antibacterial. 

Fluconazole. This substance (19) is a water-soluble bis-triazole tertiary alcohol (33). Fluconazole [86586-75-4] h.3.s a broad spectmm, but has httie activity in vitro. However, animal experiments reveal a broad spectmm and a potent effect. 

At the tested daily dose of 50 mg, fluconazole appears to be slightly less active against dermatophytes. The substance is used mainly to treat vaginal candidosis (a single capsule of 150 mg) and oral and esophageal candidosis (50 mg od for 14 d). In a number of countries, ie, England, the maximal period of treatment is 14 d. 

Toxicological studies have demonstrated that there are no important problems with fluconazole. Therapeutic doses of fluconazole may cause enzyme induction in the Hver. This suggests that interactions with other dmgs cannot be excluded. The side effects are similar to those of itraconazole and include nausea, headache, and vertigo. Occasionally, increased Hver enzymes may be noted. Like itraconazole, fluconazole is contraindicated during pregnancy. 

Fluconazole (4) (s the first member of a new generation of orally acti ve antifungal agents, highly effective in the treatment of dermal and vaginal infections [6, 7] S-Fluorocyrtosine (5) is also used to treat serious systemic fungal infections [5]... 

The Corey-Chaykovsky reaction incited some applications in medicinal chemistry. During the synthesis of analogs of fluconazole, an azole antifungal agent, treatment of 49 with 1 led to the corresponding epoxide, which was subsequently... 

The imidazoles and triazole ( azoles) (for example, ketoconazole, itraconazole (ITRA), fluconazole (FLU), voriconazole) interfere with cytochrome P45o-dependent lanosterol C14 demethylase, leading to dqDletion of ergosterol and accumulation of lanosterol in the... 

FLUCONAZOLE Because older adults are more likely to have decreased renal function, they are at increased risk for further renal impairment or renal failure. 

The primary care provider has prescribed fluconazole 200 mg PO initially, followed by 100 mg PO daily. On hand are fluconazole 100-mg tablets. What would tiie nurse administer as tiie initial dose ... 

C1H4CI2O 534-07-6) see Ebrotidine Famotidine Fluconazole Ritonavir 2, 4 -dichloroacetophenone... 

CSH4F2 372-18-9) see Fluconazole Risperidone 2,4 -difluorobenzophenone (C13HJF2O 342-25-6) see Flutrimazole 4-(2,4-difluorobenzoyl)piperidine hydrochloride (C12H14CIF2NO 106266-04-0) see Risperidone 6a,9-difIuoro-2-chloro-16(i-methyl-ljp,17-dihydroxy-21-acetoxypregna-1,4-diene-3,20-dione (C24H29CIF2O4 23961-22-0) see Halometasone... 

Clotrimazole, miconazole, econazole, ketoconazole Newer imidazoles fluconazole, itraconazole... 

Fig. 5.20 Imidazoles (A-F) A, metronidazole B, clotrimazole C, miconazole D, econazole E, ketoconazole F, fluconazole G, flucytosine H, 5-fluorouracil I, terbinafme J, tolnaftate.

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Perea S, JL Lopez-Ribot, WR Kirkpatrick, RK McAtee, RA Santillan, M Martinez, D Calabrese, D Sanglard, TP Patterson (2001) Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients. Antibicrob Agents Chemother 45 2676-2684. 

Allopurinol, barbiturates, carbamazepine, cephalosporins, cyclophosphamide, ethambutol, fluconazole, ibuprofen, lamotrigine, macrolides, nitrofurantoin, penicillins, phenytoin, propranolol, quinolones, sulfonamide antimicrobials, sulindac, tetracyclines, thiazides, valproic acid, and vancomycin... 

Chloral hydrate Chloramphenicol Cimetidine Ciprofloxacin Clofibrate Danazol Disulfiram Doxycycline Erythromycin Fenofibrate Fluconazole Fluorouracil Fluoxetine Fluvoxamine Gemfibrozil Influenza vaccine Isoniazid Itraconazole Fovastatin Metronidazole Miconazole Moxalactam Neomycin Norfloxacin Ofloxacin Omeprazole Phenylbutazone Piroxicam Propafenone Propoyxphene Quinidine Sertraline Sulfamethoxazole Sulfinpyrazone Tamoxifen Testosterone Vitamin E Zafirlukast... 

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